title: Phase I evaluation of telatinib, a VEGF receptor tyrosine kinase inhibitor, in combination with bevacizumab in subjects with advanced solid tumors.
abstract: BACKGROUND
  Blocking both receptor and ligand of the vascular endothelial growth factor (receptor) VEGF(R) pathway might be feasible and increase antitumor activity. This phase I study investigated telatinib, an oral tyrosine kinase inhibitor targeting VEGFR-2, combined with bevacizumab, in adults with solid tumors.
  
  
  METHODS
  Twenty-six patients were treated in successive cohorts with telatinib (twice-daily continuously, 450-900 mg) or bevacizumab (bi-weekly, starting dose 5 mg/kg). Safety, pharmacokinetics, endothelial (progenitor) cell (E(P)C)/growth factor kinetics and efficacy were assessed.
  
  
  RESULTS
  Most frequent adverse events were pain, nausea, voice changes and fatigue. Five dose-limiting toxicities (DLTs) occurred: hypertension (cohort I and II), bowel perforation, lipase increase and atrial flutter (cohort III). Cumulative toxicity resulted in a bevacizumab dose reduction to 1 mg/kg (cohort III). Due to three DLTs (n = 14), this cohort represented the best-tolerated dose level. Bevacizumab effectively neutralized plasma VEGF even at 1 mg/kg. Twelve patients had stable disease (clinical benefit 46%). EPC and SDF-1α levels increased during monotherapy telatinib.
  
  
  CONCLUSIONS
  Telatinib (450 mg b.i.d.) combined with bevacizumab (1 mg/kg bi-weekly) shows antitumor activity, but accumulating constitutional toxicity impedes long-term treatment of patients. Therefore, this combination will not be pursued in a phase II setting.
authors.affiliation: Department of Medical Oncology, University Medical Center Utrecht, Utrecht.
authors.forename: M H G
authors.initials: MHG
authors.lastname: Langenberg
authors.affiliation: Department of Medical Oncology, University Medical Center Utrecht, Utrecht.
authors.forename: P O
authors.initials: PO
authors.lastname: Witteveen
authors.affiliation: Department of Medical Oncology, University Medical Center Utrecht, Utrecht.
authors.forename: J
authors.initials: J
authors.lastname: Roodhart
authors.affiliation: Department of Medical Oncology, University Medical Center Utrecht, Utrecht.
authors.forename: M P
authors.initials: MP
authors.lastname: Lolkema
authors.affiliation: Department of Medical Oncology, University Medical Center Utrecht, Utrecht.
authors.forename: H M W
authors.initials: HMW
authors.lastname: Verheul
authors.affiliation: Department of Medical Oncology, The Netherlands Cancer Institute Amsterdam, Amsterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Mergui-Roelvink
authors.affiliation: Department of Pharmacokinetic Analysis, Bayer HealthCare AG, Wuppertal, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Brendel
authors.affiliation: Department of Pharmacokinetic Analysis, Bayer HealthCare AG, Wuppertal, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Krätzschmar
authors.affiliation: Bayer Schering Pharma, Mijdrecht, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Loembé
authors.affiliation: Department of Medical Oncology, The Netherlands Cancer Institute Amsterdam, Amsterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Nol-Boekel
authors.affiliation: Bayer Pharmaceuticals Inc., Montville, USA.
authors.forename: O
authors.initials: O
authors.lastname: Christensen
authors.affiliation: Department of Medical Oncology, The Netherlands Cancer Institute Amsterdam, Amsterdam, The Netherlands; Department of Pharmaceutical Sciences, Division Drug Toxicology, Utrecht University, Utrecht, The Netherlands.
authors.forename: J H M
authors.initials: JHM
authors.lastname: Schellens
authors.affiliation: Department of Medical Oncology, University Medical Center Utrecht, Utrecht. Electronic address: e.e.voest@umcutrecht.nl.
authors.forename: E E
authors.initials: EE
authors.lastname: Voest
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000068258:Bevacizumab; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011724:Pyridazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors*; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011725:Pyridines; C533371:telatinib; D000068258:Bevacizumab; C501162:FLT1 protein, human; D011505:Protein-Tyrosine Kinases; D040281:Vascular Endothelial Growth Factor Receptor-1